Modified antisense oligonucleotides (ASO) have been designed complementary to various regulatory sequences including the AP-1, SP-1, NFAT-1 and certain regulatory and structural genes of HIV-1. ASO's have also been designed to specific cellular sequences in order to understand their possible role in viral replication. These ASOs are being evaluated for anti-HIV activity using H9 and U937 cells as target cells. Antiviral activity is being assessed by p24 antigen assays and PCR. The ASOs will also be evaluated in combination with other antiviral agents that are currently in clinical trials with the objective of achieving synergy, possibly at a more physiologically tolerable dose. Similar studies will be performed with HIV-2. In other studies, the use of ribozymes to regulate viral gene expression will be explored.